Lipid metabolism disorders associated with protease inhibitor (PI) therapy is of growing concern and statin compounds such as simvastatin, pravastatin, and atorvastatin are increasingly being prescribed in persons taking PI-based potent antiretroviral therapy. It is important to determine whether there are significant drug-drug interactions between the statin compounds and protease inhibitors. The objectives of this study are to investigate the effect of ritonavir and saquinavir on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin and to evaluate the effect of pravastatin on the disposition of nelfinavir and its M8 metabolite. This trial will be conducted in an HIV-uninfected population because of the concern about developing drug resistance in persons taking protease inhibitor monotherapy. To meet the goals of objective one, 14 evaluable subjects for each cohort of Arm A will be stabilized on a fixed regimen of pravastatin, simvastatin, or atorvastatin for four days. A baseline PK evaluation of pravastatin (or simvastatin or atorvastatin) will be completed on day 4. Pravastatin (or simvastatin or atorvastatin) dosing will cease following the day 4 dose and PK evaluation. On day 5, a ritonavir and saquinavir combination regimen will be initiated and continued through day 18 of the study. Pravastatin (or simvastatin or atorvastatin) dosing will resume on day 15 and continue through day 18. A repeat PK evaluation of pravastatin (or simvastatin or atorvastatin) in the context of combination therapy will be carried out on day 18. For objective two, a two-week regimen of nelfinavir will be initiated in 14 evaluable subjects participating in Arm B. On day 14, a baseline PK profile of nelfinavir and its M8 metabolite will be carried out. Pravastatin will then be added to this regimen for study days 15 to 18. On day 18, a repeat PK evaluation of nelfinavir and the M8 metabolite will be carried out in the context of combination therapy.
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